title: Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation.
abstract: Wilson disease (WD) is caused by defects in ATP7B gene due to impairment of normal function of the copper transporting P-type ATPase. This study describes a comprehensive genetic analysis of 199 Indian WD patients including mutations detected in our previous studies, undertakes functional assessment of the nucleotide variants in ATP7B promoter and correlates genotype with disease phenotype. The patient cohort harbors a total of 10 common and 48 rare mutations in the coding region of ATP7B including 21 novel changes. The common mutations represent 74% of characterized coding mutant alleles with p.C271X (63/260) and p.G1101R (7/31) being the most prevalent in eastern and western Indian patients, respectively. The mutation spectrum between east and west is mostly different with only three mutations (p.G1061E, p.N1270S and p.A1049A-fs) being shared between both the groups. Eight novel and 10 reported variants have been detected in the promoter and non-coding regions (5' and 3'UTRs) of ATP7B. Promoter reporter assay demonstrated that 3 novel variants and 5 reported polymorphisms alter the gene expression to a considerable extent; hence might play important role in ATP7B gene regulation. We devised the neurological involvement score to capture the spectrum of neurological involvement in WD patients. By utilizing the age at onset, neurological involvement score and ATP7B mutation background, we generated a genotype-phenotype matrix that could be effectively used to depict the phenotypic spectra of WD affected individuals and serve as a platform to identify prospective "outliers" to be investigated for their remarkable phenotypic divergence.
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Shashwata
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Shruti
authors.initials: S
authors.lastname: Dutta
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Tamoghna
authors.initials: T
authors.lastname: Biswas
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Preeti
authors.initials: P
authors.lastname: Jaiswal
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Mainak
authors.initials: M
authors.lastname: Sengupta
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Calcutta National Medical College, Kolkata, India.
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Gangopadhyay
authors.affiliation: KEM Hospital, Pune, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Bavdekar
authors.affiliation: Bangur Institute of Neurosciences, Kolkata, India. Electronic address: das_sk70@hotmail.com.
authors.forename: Shyamal K
authors.initials: SK
authors.lastname: Das
authors.affiliation: CSIR-Indian Institute of Chemical Biology, Kolkata, India. Electronic address: kray@iicb.res.in.
authors.forename: Kunal
authors.initials: K
authors.lastname: Ray
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006527:Hepatolenticular Degeneration / Q000235:genetics*; D006801:Humans; D007194:India; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7B; Genotype–phenotype correlation; WD; Wilson disease